The normal morphogenesis of epithelial tissue has been suggested to be controlled by factors derived from mesenchymal cells present around the epithelial tissue. Diseases resulting from the abnormal morphogenesis of epithelial tissue are largely caused by abnormalities of mesenchymal cells. Therefore, an interest has arisen in the clarification of the mechanism in which mesenchymal cells controls the morphogenesis of epithelial tissue. However, substances involved in the control of morphogenesis of epithelial tissue are expressed under time and spatial control in a complicated system, and accordingly, it is extremely difficult to isolate these substances and analyze their functions. It is also difficult to construct a model experimental system simplifying the morphogenesis of epithelial tissue. For these reasons, no significant progress has been made to date in researches in this field. Thus, analysis of the controlling mechanism for the morphogenesis of epithelial tissue has been highly desired in order to elucidate the mechanism of occurrence of diseases associated with the morphogenesis of epithelial tissue and establish methods for treating these diseases.
Under the circumstances, epimorphin involved in the control of the morphogenesis of epithelial tissue was isolated (EP 0562123 (U.S. Pat. No. 5,726,298)). This substance, being a physiologically active substance containing a protein consisting of 277 to 289 amino acids as a core protein, was revealed to be biosynthesized mainly by mesenchymal cells. It was also found that epimorphin had the action of promoting the morphogenesis of epithelial tissue through its action on epithelial cells, and that normal tissue formation was not progressed when epimorphin failed to function.
As to the structure of epimorphin, it has been found that epimorphin molecule can be roughly divided into four fragments from a structural viewpoint (EP 0698666). That is, the polypeptide consisting of full length of epimorphin can be divided into the following four fragments, from its N-terminal, a coiled coil domain (1), a functional domain (2), a coiled coil domain (3), and hydrophobic domain at the C-terminal. In these fragments, it is suggested that the functional domain (the domain specified by 104th to 187th (from N terminal) amino acids in human epimorphin) participates in cell adhesion and is closely related with an expression of physiological activity of epimorphin (EP 0698666).
Since epimorphin has an action for promoting normal morphogenesis, this substance is expected to be useful as an active ingredient of medicaments for preventive or therapeutic treatment of diseases caused by abnormal morphogenesis, or medicaments such as a hair growth promoting agent. However, a native epimorphin obtained from a mammal is almost insoluble in an aqueous media such as saline, which causes difficulty in practically using the substance as medicaments. Some attempts were made to produce new epimorphin derivatives having good solubility while substantially keeping the promoting activity on morphogenesis of the native epimorphin. For example, a modified form (fragment 123) obtained by removing a hydrophobic region at C-terminal has been known (EP 0562123 (U.S. Pat. No. 5,726,298)).
It is also known that a polypeptide having a partial structure of epimorphin promotes morphogenesis of epithelial tissue through its action on epithelial cells (EP 1008603). This peptide is soluble in aqueous media such as saline, and the above publication teaches that this peptide has hair growth promoting activity. In addition, EP 1288221 discloses an oligopeptide having a partial structure of epimorphine, which has hair growth promoting activity.